Simian immunodeficiency virus (SIV) causes encephalopathy in juvenile rhesus monkeys. Up-regulation of somatostatin gene expression in cortical interneurons accompanies motor and cognitive impairment in rhesus monkeys, and is correlated with HIV encephalitis in human pediatric AIDS, defining a potential neuronal surrogate marker for HIV/SIV-associated CNS disease. Levels of productive virus infection in the brain are highly correlated with peripheral blood virus burden, and virus burden in other peripheral tissues, in SIV infection. However, productive virus infection in brain is not correlated with motor or cognitive impairment in SIV-infected rhesus monkeys, suggesting that proinflammatory mediators generated during virus challenge to the brain in the course of HIV/SIV infection may be the main perturbation driving CNS dysfunction. While levels of productive virus infection of the brain may not correlate with encephalopathy, decreasing virus burden may well ameliorate encephalopathy by down-regulating inflammatory processes initiated by frequent virus presentation to the brain at portals such as the choroid plexus, the blood-brain barrier, the meningio-parenchymal brain barrier, and the circumventricular organs. 6-chloro-ddG, a prototype antiretroviral prodrug with enhanced pentrance to the brain, has been shown to decrease virus burden in CSF, when administered following ddI (which possesses poor brain penetrance), to levels far lower than those achieved with ddI alone. The work of defining proinflammatory mediators whose up-regulation is triggered by virus entry into the brain and is correlated with encephalopathy can proceed from examination of CNS tissue derived from monkeys with or without AIDS and with or without encephalopathy, if mRNAs encoding these molecules (indoleamine dioxygenase, IFNgamma, TNFalpha, IL-1alpha) can be accurately quantitated in CNS tissue. A quantitative QC-PCR technique to allow this, ultimately applicable to fixed tissue sections, is being developed.